Induction of Antitumor Immunity Ex Vivo Using Dendritic Cells Transduced With Fowl Pox Vector Expressing MUC1, CEA, and a Triad of Costimulatory Molecules (rF-PANVAC)

Vasir, Baldev; Zarwan, Corrine; Ahmad, Rehan; Crawford, Keith; Rajabi, Hassan; Matsuoka, Ken; Rosenblatt, Jacalyn; Wu, Zhiyou; Mills, Heidi; Küfe, Donald; Avigan, David

doi:10.1097/cji.0b013e31826a73de

Cited by 7 publications

(3 citation statements)

References 54 publications

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“…The observation of response to the CEA peptide is encouraging since CEA is somewhat aberrantly expressed by many breast cancers, both ER positive and negative [ 50 , 51 ]. This observation that T cells could be stimulated to recognize CEA corroborates several prior CEA-based vaccines [ 52 – 55 ], most notably a CEA DNA vaccine resulted in clonal, CEA-specific T cell responses as well as B-cell responses and helper responses [ 56 ].…”

Section: Discussionsupporting

confidence: 82%

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

Dillon

Petroni

Smolkin

et al. 2017

j. immunotherapy cancer

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BackgroundBreast cancer remains a leading cause of cancer death worldwide. There is evidence that immunotherapy may play a role in the eradication of residual disease. Peptide vaccines for immunotherapy are capable of durable immune memory, but vaccines alone have shown sparse clinical activity against breast cancer to date. Toll-like receptor (TLR) agonists and helper peptides are excellent adjuvants for vaccine immunotherapy and they are examined in this human clinical trial.MethodsA vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, −A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. The vaccine was administered on days 1, 8, 15, 36, 57, 78. CD8+ T cell responses to the vaccine were assessed by both direct and stimulated interferon gamma ELIspot assays.ResultsTwelve patients with breast cancer were treated: five had estrogen receptor positive disease and five were HER2 amplified. There were no dose-limiting toxicities. Toxicities were limited to Grade 1 and Grade 2 and included mild injection site reactions and flu-like symptoms, which occurred in most patients. The most common toxicities were injection site reaction/induration and fatigue, which were experienced by 100% and 92% of participants, respectively. In the stimulated ELIspot assays, peptide-specific CD8+ T cell responses were detected in 4 of 11 evaluable patients. Two patients had borderline immune responses to the vaccine. The two peptides derived from CEA were immunogenic. No difference in immune response was evident between patients receiving endocrine therapy and those not receiving endocrine therapy during the vaccine series.ConclusionsPeptide vaccine administered in the adjuvant breast cancer setting was safe and feasible. The TLR3 adjuvant, poly-ICLC, plus helper peptide mixture provided modest immune stimulation. Further optimization is required for this multi-peptide vaccine/adjuvant combination.Trial registration ClinicalTrials.gov (posted 2/15/2012): NCT01532960. Registered 2/8/2012. https://clinicaltrials.gov/show/NCT01532960 Electronic supplementary materialThe online version of this article (10.1186/s40425-017-0295-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 82%

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

Dillon

Petroni

Smolkin

et al. 2017

j. immunotherapy cancer

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“…However, in vivo experiments within our laboratory have shown limited response to GO-201 and GO-201 demonstrates a cytotoxic effect on normal human fibroblasts (50). In addition to small-molecule inhibitors, MUC1 vaccines are also being investigated for their efficacy in multiple tumor types (51,52). Our research elucidated two novel mechanisms to target IFITM1 expression both in vitro and in vivo through treatment with estrogen or ruxolitinib.…”

Section: Muc1/ifitm1mentioning

confidence: 95%

Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor–Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis

Escher

Lui

Geanes

et al. 2019

Molecular Cancer Research

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The human oncoprotein, mucin 1 (MUC1), drives tumorigenesis in breast carcinomas by promoting epithelialto-mesenchymal transition (EMT), epigenetic reprogramming, and evasion of immune response. MUC1 interacts with STAT1, through JAK/STAT signaling, and stimulates transcription of IFN-stimulated genes, specifically IFNinduced transmembrane protein 1 (IFITM1). Our laboratory has previously shown that IFITM1 overexpression in aromatase inhibitor (AI)-resistant breast cancer cells promotes aggressiveness. Here, we demonstrate that differential regulation of MUC1 in AI-sensitive (MCF-7 and T-47D) compared with AI-resistant (MCF-7:5C) cells is critical in mediating IFITM1 expression. A tumor microarray of 94 estrogen receptor-positive human breast tumors correlated coexpression of MUC1 and IFITM1 with poor recurrence-free survival, poor overall survival, and AI-resistance. In this study, we investigated the effects of MUC1/IFITM1 on cell survival and proliferation. We knocked down MUC1 levels with siRNA and pharmacologic inhibitors, which abrogated IFITM1 mRNA and protein expression and induced cell death in AI-resistant cells. In vivo, estrogen and ruxolitinib significantly reduced tumor size and decreased expression of MUC1, P-STAT1, and IFITM1. Implications: MUC1 and IFITM1 overexpression drives AI resistance and can be targeted with currently available therapies.

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“…As shown in Figure 4 A,B, SM + M specifically upregulate 14 CDs in Tregs including immune checkpoints CD96 and PDCD1 (PD-1) [ 41 ], Treg suppression-promoting CD52 [ 78 ], and resting cluster 6 Treg marker SELL [ 14 ]. SM specifically upregulate the transcript of one CD, which is plastic Treg-promoting MUC1 [ 79 ]. M specifically upregulates the transcripts of 17 CDs including 3 chemokine receptors, 3 integrins, and TNFRSF14, a TNF receptor superfamily member.…”

Section: Resultsmentioning

confidence: 99%

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

Shao

Saaoud

Cornwell

et al. 2022

Cells

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CD4+ regulatory T cells (Tregs) respond to environmental cues to permit or suppress inflammation, and atherosclerosis weakens Treg suppression and promotes plasticity. However, the effects of smoking plus morphine (SM + M) on Treg plasticity remain unknown. To determine whether SM + M promotes Treg plasticity to T helper 17 (Th17) cells, we analyzed the RNA sequencing data from SM, M, and SM + M treated Tregs and performed knowledge-based and IPA analysis. We demonstrated that (1) SM + M, M, and SM upregulated the transcripts of cytokines, chemokines, and clusters of differentiation (CDs) and modulated the transcripts of kinases and phosphatases in Tregs; (2) SM + M, M, and SM upregulated the transcripts of immunometabolism genes, trained immunity genes, and histone modification enzymes; (3) SM + M increased the transcripts of Th17 transcription factor (TF) RORC and Tfh factor CXCR5 in Tregs; M increased the transcripts of T helper cell 1 (Th1) TF RUNX3 and Th1-Th9 receptor CXCR3; and SM inhibited Treg TGIF1 transcript; (4) six genes upregulated in SM + M Tregs were matched with the top-ranked Th17 pathogenic genes; and 57, 39 genes upregulated in SM + M Tregs were matched with groups II and group III Th17 pathogenic genes, respectively; (5) SM + M upregulated the transcripts of 70 IPA-TFs, 11 iTregs-specific TFs, and 4 iTregs-Th17 shared TFs; and (6) SM + M, M, and SM downregulated Treg suppression TF Rel (c-Rel); and 35 SM + M downregulated genes were overlapped with Rel-/- Treg downregulated genes. These results provide novel insights on the roles of SM + M in reprogramming Treg transcriptomes and Treg plasticity to Th17 cells and novel targets for future therapeutic interventions involving immunosuppression in atherosclerotic cardiovascular diseases, autoimmune diseases, transplantation, and cancers.

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Induction of Antitumor Immunity Ex Vivo Using Dendritic Cells Transduced With Fowl Pox Vector Expressing MUC1, CEA, and a Triad of Costimulatory Molecules (rF-PANVAC)

Cited by 7 publications

References 54 publications

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer

Interaction Between MUC1 and STAT1 Drives IFITM1 Overexpression in Aromatase Inhibitor–Resistant Breast Cancer Cells and Mediates Estrogen-Induced Apoptosis

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

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